Penetration Enhancer Conjugates for Macromolecule CNS Delivery
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Solution Overview
Problem
Current methods are ineffective for delivering therapeutic antigen-binding polypeptides across the blood-brain barrier for treating neurological disorders, particularly as existing penetration enhancers only facilitate the delivery of small molecules, not macromolecules.
Innovation Solution
The use of penetration enhancers like Pz-peptide or FMOC-peptide, covalently linked to antigen-binding polypeptides, for selective intranasal delivery to the central nervous system, enabling the efficient transport of large macromolecules such as scFv across epithelial layers.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If conventional penetration enhancers are used to deliver molecules across epithelial layers, then delivery of small molecules is enhanced, but delivery of macromolecules (10 kDa and larger) is not improved
Solution Approach 1:
The patent modifies the penetration enhancer molecules by conjugating them to carrier proteins (such as albumin or transferrin) to change their molecular characteristics. This parameter change allows the enhancers to interact with macromolecules and facilitate their transport across the blood-brain barrier, extending their effectiveness from small molecules to macromolecules including antibodies and antigen-binding polypeptides
Solution Approach 2:
The invention creates composite structures by conjugating penetration enhancers to carrier proteins, forming hybrid molecules that combine the membrane-penetrating capabilities of the enhancer with the macromolecular characteristics of the carrier. This composite approach enables the delivery system to transport large therapeutic proteins and antibodies across the BBB that conventional enhancers cannot deliver
2Quantity of substance
If therapeutic antigen-binding polypeptides are administered systemically, then they can reach the bloodstream, but they cannot effectively cross the blood-brain barrier to treat neurological disorders
Solution Approach 1:
The patent uses penetration enhancers as intermediary molecules that bridge the gap between the bloodstream and the CNS. These enhancers conjugate to the therapeutic polypeptides and mediate their transport across the BBB by interacting with transport mechanisms in the endothelial cells, allowing the polypeptide to reach the CNS without direct penetration capability
Solution Approach 2:
The delivery system is segmented into distinct functional components: the penetration enhancer module that handles BBB crossing, the carrier protein module that provides structural support and targeting, and the therapeutic polypeptide module that delivers the therapeutic effect. This segmentation allows each component to be optimized for its specific function while working together as an integrated delivery system
3Ease of operation
If intranasal administration is used to deliver antigen-binding polypeptides to the CNS, then selective delivery is achieved, but conventional methods fail to efficiently transport macromolecules
Solution Approach 1:
The patent modifies the molecular parameters of the penetration enhancer through conjugation to carrier proteins, changing their size, charge, and structural characteristics. These parameter changes enable the enhancer-complex to be recognized and transported by nasal epithelial transport mechanisms, facilitating efficient macromolecule delivery via the intranasal route to the CNS
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This approach allows for the convenient and efficient delivery of antigen-binding polypeptides to the CNS, effectively treating neurological disorders by achieving higher concentrations in brain tissues compared to systemic administration, while minimizing systemic exposure and side effects.
Implementation Method 1
penetration enhancers (e.g., Pz-peptide or FMOC-peptide) are capable of enhancing the specific delivery of large macromolecules (i.e., greater than 10 kDa) such as antigen-binding polypeptides (e.g. scFv) to the CNS, particularly when administered to nasal mucosa
Data Source
AI summary
The invention provides compositions and methods that enhance the delivery of large macromolecules (i.e., greater than 10 kDa), such as antigen-binding polypeptides, across tight junctions. Such methods and compositions are particularly useful for delivering therapeutic antigen-binding polypeptides to the CNS, via intranasal administration, for the treatment of neurological disorders.